Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

VII. Mechanism of Thyroid Hormone Action
627
TBG is the major binding protein for hormone, but not
all species have TBG. In those species without TBG, albumin
serves as the major binding protein. The binding constant
of TBG for T 4 is about 10 10 liter/mole so that some
99.97% of the plasma T 4 is bound to TBG and only 0.03%
is free or unbound (fT 4 ). The binding constant for T 3 is
about 10 9 liter/mole so that about 99.7% of the plasma T 3 is
bound to TBG and 0.3% is free. Therefore, TBG or albumin
transports most of the hormones.
In the cat, rabbit, rat, mouse, guinea pig, pigeon, or
chicken, TBG is absent and most of the hormone is transported
by albumin. The albumin binding constant is about
10 5 liter/mole for T 4 or T 3 but with an unlimited binding
capacity. In these species without TBG, albumin transports
between 50% and 80% of the hormones. T 3 (and likely
rT 3 ) appears to bind to these transport proteins in parallel
with T 4 binding.
Protein binding has several functions. Protein binding
solubilizes these lipid soluble hormones for transport in
the aqueous plasma. The bound forms also do not readily
pass through the renal glomerular membrane, so they minimize
urinary loss of hormones, whereas the free hormones
pass and are lost. The bound forms also serve as a large
and readily accessible reservoir of the active hormones for
delivery to the target organs and cells. Finally, the protein
binding equilibrium is the fundamental basis for protein or
immunoprotein binding assays of hormone and the indirect
assay of TBG.
VII . MECHANISM OF THYROID HORMONE
ACTION
A . General Effects of Thyroid Hormones
After the administration of thyroid extracts or T 4 , its first
physiological effects are noted in 24 to 28 h and its maximal
effects are noted in 7 to 10 days ( Table 20-2 ). The T 4
requirements for these effects vary. The requirement for
T 3 also varies, and less is required for equivalent activity
and it acts more quickly. T 3 is now recognized as the active
form of the thyroid hormone within the target cell. The T 4
that is transported into the target cell is rapidly deiodinated
to the active T 3 . However, rT 3 , which is also produced in
the cell in the deiodination process, is an inactive form of
thyroid hormone and is simply degraded.
B . Molecular Basis of Thyroid Hormone
Action
The molecular basis of thyroid hormone action at the cellular
level has been frequently reviewed, and a multifaceted
concept of its action has evolved. For many years,
the mitochondrion was considered to be the site of thyroid
hormone action. Uncoupling of oxidative phosphorylation
(ox-phos) in the mitochondria was a viable hypothesis for
many years. Under normal conditions, 3 moles of ATP (P)
are synthesized per atom of oxygen (½ 0 2 0) used in
the cytochrome oxidase system; hence, P:0 ratio equals 3.
If less than 3 moles of ATP are formed per unit 0 in a system
in the presence of a compound such as the thyroid
hormone, the system is said to be uncoupled (i.e., P:0 ratio
is less than 3). In this event, more O 2 would be needed to
generate an equivalent amount of ATP, and O 2 consumption
would increase. T 4 has repeatedly been shown to uncouple
oxidative phosphorylation in in vitro systems, but it does
so only in large, unphysiological amounts. These findings
were extended to the whole animal to explain the increased
oxygen consumption by T 4 . The large amounts of oxidative
energy not incorporated into ATP increased body temperature
and were dissipated as heat. Thus, T 4 action was
theorized to be the result of the uncoupling of oxidative
phosphorylation.
Another now well-known effect of thyroid hormone is
the stimulation of cellular protein synthesis ( Tapley, 1964 ;
Tata et al., 1963 ), and this occurs during the latent period
when the calorigenic effect of thyroid hormone occurs.
T 3 is now known to stimulate messenger RNA (mRNA)
transcription, increasing translation and protein synthesis
and accounting for the anabolic effects of thyroid hormones.
This also means that the site of action is at the cell
nucleus.
Another action of thyroid hormone is to stimulate the
“ sodium pump ” (Na-K-ATPase) at the cell membrane,
an action that would increase O 2 consumption ( Edelman,
1974 ). Ouabain, an inhibitor of Na-K-ATPase, also inhibits
the increased O 2 consumption induced by T 4 or T 3 . Thus,
stimulation of the sodium pump is an important way in
which thyroid hormones stimulate increased oxygen consumption
and accounts for almost half of the increase.
TABLE 20-2 Effects of Thyroid Hormone
Category
Clinical
Physiological
Calorigenic
Carbohydrate
metabolism
Protein metabolism
Lipid metabolism
Development
Reproductive
Hematological
Effect
Tremors, nervousness, exophthalmos,
hyperactivity, weight loss
Increased temperature, heart function
Increased basal metabolic rate
(O 2 consumption)
Increased glucose turnover, absorption
Anabolic, positive N balance
Decrease in blood cholesterol
Stimulation of growth and maturation
Fertility, pregnancy, ovulation
Erythropoiesis